Referred scheduling proposal

The New Chemical Entity (NCE) delegate from the Therapeutic Goods Administration has referred the substance guanfacine hydrochloride, proposing that the substance be listed in Appendix K.

Current scheduling status and relevant scheduling history

Guanfacine hydrochloride is not currently scheduled in Australia and has not been previously considered for scheduling; a scheduling history is therefore not available.

International regulatory information

Guanfacine hydrochloride is not classified in New Zealand. In the USA and Canada, Guanfacine hydrochloride is classified as a Prescription Only medicine.

Scheduling application

The proposed amendment to the Poisons Standard is as follows:

Schedule 4 - Proposed New Entry

GUANFACINE HYDROCHLORIDE.

Appendix K - Proposed New Entry

GUANFACINE HYDROCHLORIDE

The reason provided by the clinical delegate is on the basis that guanfacine hydrochloride causes sedation.

Substance summary

Guanfacine hydrochloride (Figure 3.11, Table 3.11) is a central alpha2A-adrenergic receptor agonist and is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in paediatric patients (children and adolescents 6-17 years old inclusive).

Figure 3.11: Structure of guanfacine hydrochloride

Guanfacine hydrochloride is not a central nervous system (CNS) stimulant, a monoamine transporter inhibitor or releaser of presynaptic dopamine or norepinephrine. The mode of action of guanfacine hydrochloride in ADHD is not fully established. Preclinical research suggests guanfacine hydrochloride modulates signalling in the prefrontal cortex and basal ganglia through direct modification of synaptic norepinephrine transmission at the alpha 2-adrenergic receptors. The INN is guanfacine[13].

There is a USP 36 monograph for guanfacine hydrochloride, but no BP 2016 monograph.

Table 3.11: General information for guanfacine hydrochloride

Property

Guanfacine hydrochloride

Australian Approved name (AAN)

guanfacine hydrochloride (reference USP, USAN)

CAS No.

29110-48-3

Chemical name

N-amidino-2-(2,6-dichlorophenyl)acetamide monohydrochloride

Molecular formula

C9H9Cl2N3O.HCl

Molecular weight

282.6 g/mol (for the hydrochloride salt)

Form

White to off-white powder (single polymorphic form)

Solubility

sparingly soluble in water and alcohol and slightly soluble in acetone

Partition coefficient (logP)

2-octanol/water: 0.10

Dissociation constant

7.69

pH

~4 when dissolved in water

Pre-meeting public submissions

No pre-meeting submissions were received for guanfacine.

Summary of ACMS advice to the delegate

The committee advised that guanfacine should be entered in Schedule 4 with an Appendix K listing.

The recommended wording for the guanfacine entry is as follows:

Schedule 4 - New Entry

GUANFACINE.

Appendix K - New Entry

GUANFACINE.

The Committee also recommended an implementation date of 1 June 2017.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: a) the risks and benefits of the use of a substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the advice comprised the following:

Guanfacine is a central alpha2A-adrenergic receptor agonist used in the treatment of ADHD in children and adolescents.

Guanfacine hydrochloride carries a significant risk of causing sedation and somnolence in humans exhibited by a medicine in normal use. Data demonstrates impairment of critical motor reflexes and cognitive skills applicable to driving or the operation of machinery with guanfacine hydrochloride use and therefore there is a need to warn users of any potential danger of the medication.

There are no products containing guanfacine hydrochloride currently registered in the ARTG. This is a prescription-only medicine and Appendix K sedation warning is appropriate.

Guanfacine hydrochloride has no known potential for abuse or dependence. The current sedation warning statements are more appropriate for a medication used in adults rather than children and adolescents.

Delegate's interim decision

The delegate's interim decision is that a new Schedule 4 entry for guanfacine with an Appendix K listing is appropriate.

The proposed Schedule entry is as follows:

Schedule 4 - New Entry

GUANFACINE.

Appendix K - New Entry

GUANFACINE.

The proposed implementation date is 1 June 2017.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; and f) any other matters that the Secretary considers necessary to protect public health.